The variolins are a new class of marine alkaloids isolated from the rare, difficult to access Antarctic sponge Kirkpatricka varialosa, with Variolin B (1) being a typical example.
The variolins all contain a fused pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine core (2), with either a heterocyclic aromatic ring or an ester group attached at C5, as in Variolin B (1) and Variolin D (3).

The variolins are disclosed to have antitumour activity and other useful properties. The complete structure, and antitumour activity, of these and related compounds is described by N. B. Perry et al. Tetrahedron, 1994, 50, 3987-92, and G. Trimurtulu et al, Tetrahedron, 1994, 50, 3993-4000. However, the variolins described in these documents have hitherto only been demonstrated to exhibit a limited range of antitumour activity.
The limited availability of natural material has resulted in the search for alternative synthetic methods being sought for the natural compounds and related analogs.
A synthetic process for producing the related deoxyvariolin B (4) has been described by M. Alvarez et al, Tetrahedron Lett., 2001, 42, 315-317 (which was published before the filing date of the present application but after the priority dates).

The route to deoxyvariolin B described in this reference involves a total of at least fourteen steps, in which the fused tricyclic pyridopyrrolopyrimidine core is constructed from a 7-azaindole and a heteroaryl coupling reaction is then used to introduce the fourth aromatic ring to give intermediate (5). Substitution of the derived sulphone group (6) for an amino group gave deoxyvariolin B (4):

However, as noted above, this synthesis is long and complex. Further, no synthetic process has been reported for variolin B (or any of the natural variolins).
It is therefore desirable to provide a process capable of synthesising deoxyvariolin B and derivatives thereof in a smaller number of steps than the process described above.
It is also desirable to provide a process capable of synthesising variolin B itself as well as the deoxy derivative.
It is further desirable to provide new compounds having antitumour activity comparable or superior to natural variolin B.
The synthetic methods of the present invention provide the first method for preparation of variolin B (1) and provide short, rapid entry to deoxyvariolin B (4) and intermediates such as (5) and (6). These intermediates have been used in the preparation of new antitumour compounds containing the fused tricyclic pyridopyrrolopyrimidine core of the variolins.